Drug overdose is the leading cause of injury death among adults aged 25 to 64 years in the United States. The number of fatal overdoses involving opioid pain relievers nearly quadrupled between 1999 and 2013, and fatal overdoses related to heroin almost tripled between 2010 and 2013. Public health interventions designed to reduce opioid overdose deaths are urgently needed. Naloxone is an opioid antagonist that reverses opioid overdoses. Increased access to naloxone has been shown to reduce opioid overdose mortality; however, naloxone is a prescription drug, which limits opportunities to expand its distribution. In March 2014, Massachusetts established an innovative program that allows the issuance of naloxone standing orders (NSO) at community pharmacies. Under NSO, pharmacies can dispense naloxone to any individual at risk of having, or witnessing, an opioid overdose. Massachusetts is one of the first states to implement a pharmacy-based naloxone distribution program on a broad scale, but a growing number of states are passing legislation to authorize these programs. Accordingly, Massachusetts represents an important and timely natural experiment in expanding naloxone access through community pharmacies. This study will use a multiphase mixed methods research design to assess the implementation and impact of the Massachusetts NSO program. Specifically, this study will (1) characterize implementation of the Massachusetts NSO program and assess barriers and facilitators to pharmacy participation and proper dispensing; (2) examine the acceptability of pharmacy-based naloxone dispensing to illicit opioid users and potential overdose bystanders and identify factors that would increase acceptance for these two groups; and (3) assess the impact of the pharmacy NSO program on overdose mortality. At the conclusion of our study, we will have generated a comprehensive understanding of the factors that influence the implementation and impact of one of the first statewide pharmacy-based naloxone dispensing programs in the United States. Our findings will be of considerable value to the growing number of states considering and/or implementing NSO programs as part of their overall strategy to reduce the public health burden of opioid overdose mortality.